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Function and location

The gastric hydrogen potassium ATPase or H+/K+ ATPase is the proton pump of the stomach and as such is the enzyme primarily responsible for the acidification of the stomach contents (see gastric acid). The H+/K+ ATPase is found in parietal cells which are highly specialised epithelial cells located in the inner cell lining of the stomach, which is called the gastric mucosa. Parietal cells possess an extensive secretory membrane system and the H+/K+ ATPase is the major protein constituent of these membranes.

Genes and Protein structure

The H+/K+ ATPase is a heterodimeric protein, the product of 2 genes. The gene ATP4A encodes the H+/K+ ATPase α subunit contains and is an ~ 1000 amino acid protein that contains the catalytic sites of the enzyme and forms the pore through the cell membrane that allows the transport of ions. The gene ATP4B encodes the β subunit of the H+/K+ ATPase, which is an ~ 300 amino acid protein with a 36 amino acid N-terminal cytoplasmic domain, a single transmembrane domain, and a highly glycosylated extracellular domain. The H+/K+ ATPase β subunit stabilizes the H+/K+ ATPase α subunit and is required for function of the enzyme. It also appears to contain signals that direct the heterodimer to membrane destinations within the cell, although some of these signals are subordinate to signals found in H+/K+ ATPase α subunit.

Enzyme activity of the H+/K+ ATPase

The H+/K+ ATPase is a member of the P-type ATPase superfamily, a large family of related proteins that transport ions, most usually cations, across biological membranes in nearly all species. The H+/K+ ATPase transports one hydrogen ion (H+) from the cytoplasm of the parietal cell in exchange for one potassium ion (K+) retrieved from the gastric lumen. As an ion pump the H+/K+ ATPase is able to transport ions against a concentration gradient using energy derived from the hydrolysis of ATP. Like all P-type ATPases a phosphate group is transferred form adenosine triphosphate (ATP) to the H+/K+ ATPase during the transport cycle. This phosphate transfer powers a conformational change in the enzyme that helps drive ion transport.

Inhibition of H+/K+ ATPase

Inhibiting gastric acid secretion by blocking the activity is a very common clinical intervention used in diseases including dyspepsia, peptic ulcer disease and gastroesophageal reflux disease (GORD/GERD). Two drug categories are commonly used to inhibit H+/K+ ATPase activity. H2-receptor antagonists inhibit the signalling pathway that leads to activation of the ATPase. Proton pump inhibitors (PPIs) directly bind to and inactivate the H+/K+ ATPase.